Neurostimulator with titration assist

ABSTRACT

A method of neurostimulation titration includes titrating a neurostimulation signal from a first set of parameters toward a target set of parameters according to a titration aggressiveness profile having a titration hold point. The method further includes receiving a hold indicator indicating that the titration has reached the titration hold point. The method further includes initiating an intermediate hold of the titrating of the neurostimulation signal in response to receiving the hold indicator. The method further includes receiving an indication of a titration resumption that discontinues the intermediate hold.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.17/503,094, filed Oct. 15, 2021, which is a continuation of U.S.application Ser. No. 16/185,838, filed Nov. 9, 2018, granted as U.S.Pat. No. 11,147,972, which is a continuation of U.S. application Ser.No. 15/181,177, filed Jun. 13, 2016, granted as U.S. Pat. No.10,124,170, all of which are incorporated herein by reference in theirentireties.

BACKGROUND

The present disclosure relates generally to neurostimulation and, morespecifically, to improved systems and methods for managing titration ofstimulation.

Chronic heart failure (CHF) and other forms of chronic cardiacdysfunction (CCD) may be related to an autonomic imbalance of thesympathetic and parasympathetic nervous systems that, if left untreated,can lead to cardiac arrhythmogenesis, progressively worsening cardiacfunction and eventual patient death. CHF is pathologically characterizedby an elevated neuroexitatory state and is accompanied by physiologicalindications of impaired arterial and cardiopulmonary baroreflex functionwith reduced vagal activity.

CHF triggers compensatory activations of the sympathoadrenal(sympathetic) nervous system and the renin-angiotensin-aldosteronehormonal system, which initially helps to compensate for deterioratingheart-pumping function, yet, over time, can promote progressive leftventricular dysfunction and deleterious cardiac remodeling. Patientssuffering from CHF are at increased risk of tachyarrhythmias, such asatrial fibrillation (AF), ventricular tachyarrhythmias (ventriculartachycardia (VT) and ventricular fibrillation (VF)), and atrial flutter,particularly when the underlying morbidity is a form of coronary arterydisease, cardiomyopathy, mitral valve prolapse, or other valvular heartdisease. Sympathoadrenal activation also significantly increases therisk and severity of tachyarrhythmias due to neuronal action of thesympathetic nerve fibers in, on, or around the heart and through therelease of epinephrine (adrenaline), which can exacerbate analready-elevated heart rate.

The standard of care for managing CCD in general continues to evolve.For instance, new therapeutic approaches that employ electricalstimulation of neural structures that directly address the underlyingcardiac autonomic nervous system imbalance and dysregulation have beenproposed. In one form, controlled stimulation of the cervical vagusnerve beneficially modulates cardiovascular regulatory function. Vagusnerve stimulation (VNS) has been used for the clinical treatment ofdrug-refractory epilepsy and depression, and more recently has beenproposed as a therapeutic treatment of heart conditions such as CHF.

VNS therapy commonly requires implantation of a neurostimulator, asurgical procedure requiring several weeks of recovery before theneurostimulator can be activated and a patient can start receiving VNStherapy. Even after the recovery and activation of the neurostimulator,a full therapeutic dose of VNS is not immediately delivered to thepatient to avoid causing significant patient discomfort and otherundesirable side effects. Instead, to allow the patient to adjust to theVNS therapy, a titration process is utilized in which the intensity isgradually increased over a period of time under a control of aphysician, with the patient given time between successive increases inVNS therapy intensity to adapt to the new intensity. As stimulation ischronically applied at each new intensity level, the patient's tolerancethreshold, or tolerance zone boundary, gradually increases, allowing foran increase in intensity during subsequent titration sessions. Thetitration process can take significantly longer in practice because theincrease in intensity is generally performed by a physician or otherhealthcare provider, and thus, for every step in the titration processto take place, the patient has to visit the provider's office to havethe titration adjustments performed. Scheduling conflicts in theprovider's office may increase the time between titration sessions,thereby extending the overall titration process, during which thepatient in need of VNS does not receive the VNS at the full therapeuticintensity.

For patients receiving VNS therapy for the treatment of epilepsy, atitration process that continues over an extended period of time, suchas six to twelve months, may be somewhat acceptable because thepatient's health condition typically would not worsen in that period oftime. However, for patients being treated for other health conditions,such as CHF, the patient's condition may degrade rapidly if leftuntreated. As a result, there is a much greater urgency to completingthe VNS titration process when treating a patient with a time-sensitivecondition, such as CHF.

Accordingly, a need remains for an approach to efficiently titrateneurostimulation therapy for treating chronic cardiac dysfunction andother conditions while minimizing side effects and related discomfortcaused by the titration or by the VNS therapy itself.

SUMMARY

Systems and methods are provided for delivering neurostimulationtherapies to patients. A titration process is used to gradually increasethe stimulation intensity to a desired therapeutic level. This titrationprocess can minimize the amount of time required to complete titrationso as to begin delivery of the stimulation at therapeutically desirablelevels.

One embodiment relates to a method of performing a neurostimulationtitration. The method may include the titrating of a neurostimulationsignal delivered to a patient from an implantable pulse generator, withthe neurostimulation signal being delivered according to a first set ofparameters and then according to a second set of parameters. The firstset of parameters may have a first value for output current, frequency,pulse width, and/or duty cycle, and the second set of parameters mayhave a second value for output current, frequency, pulse width, and/orduty cycle, and the second value may be greater in magnitude than thefirst value. The method includes receiving a hold indicator that isassociated with a pre-defined titration hold point and/or an indicationof a side effect experienced by the patient in response to theneurostimulation signal. An intermediate hold in the titration may beinitiated with the intermediate hold for the pre-defined titration holdpoint being a continuation of the second parameter set neuromodulationsignal and with the intermediate hold for the side effect indicationbeing a return to the neuromodulation signal conforming with the firstset of parameters. A receipt of an indication of a titration resumptionmay result in the discontinuation of the intermediate hold. The methodcan continue with a subsequent delivering of the neurostimulation signalin conformance with the second or third set of parameters, and then amodifying of the neurostimulation signal to a third or four set ofparameters, respectively, with the third or fourth set of parametershaving a greater magnitude for output current, frequency, pulse width,and/or duty cycle as compared to the second value. The method cancontinue with the receipt of another hold indicator associated with thepre-defined titration hold point and/or another indication of anotherside effect, and may lead to an initiation of another intermediate holdfor the pre-defined titration hold point that continues the delivery ofthe prior neurostimulation signal, and that may lead to the ignition ofthe another intermediate hold for the indication of the another sideeffect that returns the neuromodulation signal to the second or thirdset of parameters, until receipt of another indication of a titrationresumption that discontinues the another intermediate hold.

Another embodiment relates to a neurostimulation system. The system mayinclude a neurostimulation system that is capable of providing aneurostimulation signal to a patient, with the neurostimulation systemhaving an implantable pulse generator that generates theneurostimulation signal according to a titration protocol that manages atitrating of the neurostimulation signal, an electrode configured todeliver the neurostimulation signal to the patient, and a lead couplingthe electrode to the implantable pulse generator. The processor may beconfigured to implement the titration protocol by issuing controlsignals that allow the implantable pulse generator to deliver theneurostimulation signal in conformance with a first set of parametersand then modifying the neurostimulation signal to conform with a secondset of parameters. The first and second sets of parameters may havefirst and second values for output current, frequency, pulse width,and/or duty cycle, and the second value may be greater in magnitude thanthe first value. The implementation of the titration protocol maycontinue with the receipt of a hold indicator that is associated with apre-defined titration hold point and/or an indication of a side effect,and lead to the initiation of an intermediate hold for the pre-definedtitration hold point that continues the prior neurostimulation signal,and lead to the initiation of the intermediate hold for the indicationof the side effect that returns to the neuromodulation signal conformingwith the first set of parameters, until the receipt of indication of atitration resumption that discontinues the intermediate hold. Theimplementation of the titration protocol may continue with additionalcontrol signals prompting the delivery of the neurostimulation signal inconformance with the second set or a third set of parameters subsequentto the receipt of the indication of the titration resumption, and themodification of the neurostimulation signal to conform with a third setor fourth of parameters, with the third or fourth set of parametershaving a values that are greater in magnitude than the second or thirdsets respectively. The processor may receive another hold indicatorassociated with the pre-defined titration hold point and/or anindication of a side effect, and initiate another intermediate hold forthe pre-defined titration hold point that is a continuation of the priorneurostimulation signal and that may initiation the another immediatehold for the indication of the another side effect that is a return tothe neuromodulation signal conforming with the second or third set ofparameters, until receiving another indication of a titration resumptionthat discontinues the another intermediate hold.

In further variations of the above-described method and system, thereceipt of the indication of the titration resumption may be preceded bya time interval sufficient to allow the patient to obtain assistancefrom a health care provider and/or activate a sensor communicating withthe implantable pulse generator. In further variations, the pre-definedtitration hold point is a time elapsed since an initiation of atitration sequence, a magnitude of a change in amplitude, an amplitudevalue, a magnitude of a change in pulse width, and/or a pulse widthvalue. In still further variations, the pre-defined titration hold pointcorresponds to a titration aggressiveness profile having a moreaggressive level and a less aggressive level, with the more aggressivelevel defined by (relative to the less aggressive level) a shorter timeinterval between parameter changes, a greater target intensity, and/or agreater increment value between parameter changes.

The foregoing summary is illustrative only and is not intended to be inany way limiting. In addition to the illustrative aspects, embodiments,and features described above, further aspects, embodiments, and featureswill become apparent by reference to the drawings and the followingdetailed description.

BRIEF DESCRIPTION OF THE DRAWINGS

Further features, characteristics and advantages of the presentdisclosure will become apparent to a person of ordinary skill in the artfrom the following detailed description of embodiments of the presentdisclosure, made with reference to the drawings annexed, in which likereference characters refer to like elements.

FIG. 1 is a front anatomical diagram showing, by way of example,placement of an implantable vagus stimulation device in a male patient,in accordance with one embodiment.

FIGS. 2A and 2B are diagrams respectively showing the implantableneurostimulator and the stimulation therapy lead of FIG. 1 , accordingto an exemplary embodiment.

FIG. 3 is a diagram showing an external programmer for use with theimplantable neurostimulator of FIG. 1 , according to an exemplaryembodiment.

FIG. 4 is a diagram showing electrodes provided as on the stimulationtherapy lead of FIG. 2 in place on a vagus nerve in situ, according toan exemplary embodiment.

FIG. 5 is a flowchart of a method for delivering vagus nerve stimulationtherapy, according to an exemplary embodiment.

FIGS. 6A and 6B are flowcharts of a titration process, according to anexemplary embodiment.

FIGS. 7A and 7B are block diagrams of neurostimulation systems,according to an exemplary embodiment.

DETAILED DESCRIPTION

Various aspects of the disclosure will now be described with regard tocertain examples and embodiments, which are intended to illustrate butnot to limit the disclosure. Nothing in this disclosure is intended toimply that any particular feature or characteristic of the disclosedembodiments is essential. The scope of protection is defined by theclaims that follow this description and not by any particular embodimentdescribed herein. Before turning to the figures, which illustrateexample embodiments in detail, it should be understood that theapplication is not limited to the details or methodology set forth inthe description or illustrated in the figures. It should also beunderstood that the terminology is for the purpose of description onlyand should not be regarded as limiting.

CHF and other cardiovascular diseases cause derangement of autonomiccontrol of the cardiovascular system, favoring increased sympathetic anddecreased parasympathetic central outflow. These changes are accompaniedby elevation of basal heart rate arising from chronic sympathetichyperactivation along the neurocardiac axis.

The vagus nerve is a diverse nerve trunk that contains both sympatheticand parasympathetic fibers, and both afferent and efferent fibers. Thesefibers have different diameters and myelination, and subsequently havedifferent activation thresholds. This results in a graded response asintensity is increased. Low intensity stimulation results in aprogressively greater tachycardia, which then diminishes and is replacedwith a progressively greater bradycardia response as intensity isfurther increased. Peripheral neurostimulation therapies that target thefluctuations of the autonomic nervous system have been shown to improveclinical outcomes in some patients. Specifically, autonomic regulationtherapy results in simultaneous creation and propagation of efferent andafferent action potentials within nerve fibers comprising the cervicalvagus nerve. The therapy directly improves autonomic balance by engagingboth medullary and cardiovascular reflex control components of theautonomic nervous system. Upon stimulation of the cervical vagus nerve,action potentials propagate away from the stimulation site in twodirections, efferently toward the heart and afferently toward the brain.Efferent action potentials influence the intrinsic cardiac nervoussystem and the heart and other organ systems, while afferent actionpotentials influence central elements of the nervous system.

An implantable vagus nerve stimulator, such as used to treatdrug-refractory epilepsy and depression, can be adapted for use inmanaging chronic cardiac dysfunction (CCD) through therapeuticbi-directional vagus nerve stimulation. FIG. 1 is a front anatomicaldiagram showing, by way of example, placement of an implantable medicaldevice (e.g., a vagus nerve stimulation (VNS) system 11, as shown inFIG. 1 ) in a male patient 10, according to an exemplary embodiment. TheVNS provided through the stimulation system 11 operates under severalmechanisms of action. These mechanisms include increasingparasympathetic outflow and inhibiting sympathetic effects by inhibitingnorepinephrine release and adrenergic receptor activation. Moreimportantly, VNS triggers the release of the endogenous neurotransmitteracetylcholine and other peptidergic substances into the synaptic cleft,which has several beneficial anti-arrhythmic, anti-apoptotic, andanti-inflammatory effects as well as beneficial effects at the level ofthe central nervous system.

The implantable vagus stimulation system 11 comprises an implantableneurostimulator or pulse generator 12 and a stimulating nerve electrodeassembly 125. The neurostimulator or pulse generator may be a voltagestimulator or, more preferably, a current stimulator. The stimulatingnerve electrode assembly 125, comprising at least an electrode pair, isconductively connected to the distal end of an insulated, electricallyconductive lead assembly 13 and electrodes 14. The electrodes 14 may beprovided in a variety of forms, such as, e.g., helical electrodes, probeelectrodes, cuff electrodes, as well as other types of electrodes.

The implantable vagus stimulation system 11 can be remotely accessedfollowing implant through an external programmer, such as the programmer40 shown in FIG. 3 and described in further detail below. The programmer40 can be used by healthcare professionals to check and program theneurostimulator 12 after implantation in the patient 10 and to adjuststimulation parameters during the stimulation titration process. In someembodiments, an external magnet may provide basic controls. For example,an electromagnetic controller may enable the patient 10 or healthcareprofessional to interact with the implanted neurostimulator 12 toexercise increased control over therapy delivery and suspension. Forfurther example, an external programmer may communicate with theneurostimulation system 11 via other wired or wireless communicationmethods, such as, e.g., wireless RF transmission. Together, theimplantable vagus stimulation system 11 and one or more of the externalcomponents form a VNS therapeutic delivery system.

The neurostimulator 12 is typically implanted in the patient's right orleft pectoral region generally on the same side (ipsilateral) as thevagus nerve 15, 16 to be stimulated, although otherneurostimulator-vagus nerve configurations, including contra-lateral andbi-lateral are possible. A vagus nerve typically comprises two branchesthat extend from the brain stem respectively down the left side andright side of the patient, as seen in FIG. 1 . The electrodes 14 aregenerally implanted on the vagus nerve 15, 16 about halfway between theclavicle 19 a-b and the mastoid process. The electrodes may be implantedon either the left or right side. The lead assembly 13 and electrodes 14are implanted by first exposing the carotid sheath and chosen branch ofthe vagus nerve 15, 16 through a latero-cervical incision (perpendicularto the long axis of the spine) on the ipsilateral side of the patient'sneck 18. The helical electrodes 14 are then placed onto the exposednerve sheath and tethered. A subcutaneous tunnel is formed between therespective implantation sites of the neurostimulator 12 and helicalelectrodes 14, through which the lead assembly 13 is guided to theneurostimulator 12 and securely connected.

In one embodiment, the neural stimulation is provided as a low levelmaintenance dose independent of cardiac cycle. The stimulation system 11bi-directionally stimulates either the left vagus nerve 15 or the rightvagus nerve 16. However, it is contemplated that multiple electrodes 14and multiple leads 13 could be utilized to stimulate simultaneously,alternatively or in other various combinations. Stimulation may bethrough multimodal application of continuously-cycling, intermittent andperiodic electrical stimuli, which are parametrically defined throughstored stimulation parameters and timing cycles. Both sympathetic andparasympathetic nerve fibers in the vagosympathetic complex arestimulated. Generally, cervical vagus nerve stimulation results inpropagation of action potentials from the site of stimulation in abi-directional manner. The application of bi-directional propagation inboth afferent and efferent directions of action potentials withinneuronal fibers comprising the cervical vagus nerve improves cardiacautonomic balance. Afferent action potentials propagate toward theparasympathetic nervous system's origin in the medulla in the nucleusambiguus, nucleus tractus solitarius, and the dorsal motor nucleus, aswell as towards the sympathetic nervous system's origin in theintermediolateral cell column of the spinal cord. Efferent actionpotentials propagate toward the heart 17 to activate the components ofthe heart's intrinsic nervous system. Either the left or right vagusnerve 15, 16 can be stimulated by the stimulation system 11. The rightvagus nerve 16 has a moderately lower (approximately 30%) stimulationthreshold than the left vagus nerve 15 for heart rate effects at thesame stimulation frequency and pulse width.

The VNS therapy is delivered autonomously to the patient's vagus nerve15, 16 through three implanted components that include a neurostimulator12, lead assembly 13, and electrodes 14. FIGS. 2A and 2B are diagramsrespectively showing the implantable neurostimulator 12 and thestimulation lead assembly 13 of FIG. 1 . In one embodiment, theneurostimulator 12 can be adapted from a VNS Therapy Demipulse Model 103or AspireSR Model 106 pulse generator, manufactured and sold byCyberonics, Inc., Houston, TX, although other manufactures and types ofimplantable VNS neurostimulators could also be used. The stimulationlead assembly 13 and electrodes 14 are generally fabricated as acombined assembly and can be adapted from a Model 302 lead, PerenniaDURAModel 303 lead, or PerenniaFLEX Model 304 lead, also manufactured andsold by Cyberonics, Inc., in three sizes based, for example, on ahelical electrode inner diameter, although other manufactures and typesof single-pin receptacle-compatible therapy leads and electrodes couldalso be used.

Referring first to FIG. 2A, the system 20 may be configured to providemultimodal vagus nerve stimulation. In a maintenance mode, theneurostimulator 12 is parametrically programmed to delivercontinuously-cycling, intermittent and periodic ON-OFF cycles of VNS.Such delivery produces action potentials in the underlying nerves thatpropagate bi-directionally, both afferently and efferently.

The neurostimulator 12 includes an electrical pulse generator that istuned to improve autonomic regulatory function by triggering actionpotentials that propagate both afferently and efferently within thevagus nerve 15, 16. The neurostimulator 12 is enclosed in a hermeticallysealed housing 21 constructed of a biocompatible material, such astitanium. The housing 21 contains electronic circuitry 22 powered by abattery 23, such as a lithium carbon monofluoride primary battery or arechargeable secondary cell battery. The electronic circuitry 22 may beimplemented using complementary metal oxide semiconductor integratedcircuits that include a microprocessor controller that executes acontrol program according to stored stimulation parameters and timingcycles; a voltage regulator that regulates system power; logic andcontrol circuitry, including a recordable memory 29 within which thestimulation parameters are stored, that controls overall pulse generatorfunction, receives and implements programming commands from the externalprogrammer, or other external source, collects and stores telemetryinformation, processes sensory input, and controls scheduled andsensory-based therapy outputs; a transceiver that remotely communicateswith the external programmer using radio frequency signals; an antenna,which receives programming instructions and transmits the telemetryinformation to the external programmer; and a reed switch 30 thatprovides remote access to the operation of the neurostimulator 12 usingan external programmer, a simple patient magnet, or an electromagneticcontroller. The recordable memory 29 can include both volatile (dynamic)and non-volatile/persistent (static) forms of memory, within which thestimulation parameters and timing cycles can be stored. Other electroniccircuitry and components are possible.

The neurostimulator 12 includes a header 24 to securely receive andconnect to the lead assembly 13. In one embodiment, the header 24encloses a receptacle 25 into which a single pin for the lead assembly13 can be received, although two or more receptacles could also beprovided, along with the corresponding electronic circuitry 22. Theheader 24 may internally include a lead connector block (not shown), asetscrew, and a spring contact (not shown) that electrically connects tothe lead ring, thus completing an electrical circuit.

In some embodiments, the housing 21 may also contain a heart rate sensor31 that is electrically interfaced with the logic and control circuitry,which receives the patient's sensed heart rate as sensory inputs. Theheart rate sensor 31 monitors heart rate using an ECG-type electrode.Through the electrode, the patient's heart beat can be sensed bydetecting ventricular depolarization. In a further embodiment, aplurality of electrodes can be used to sense voltage differentialsbetween electrode pairs, which can undergo signal processing for cardiacphysiological measures, for instance, detection of the P-wave, QRScomplex, and T-wave. The heart rate sensor 31 provides the sensed heartrate to the control and logic circuitry as sensory inputs that can beused to determine the onset or presence of arrhythmias, particularly VT,and/or to monitor and record changes in the patient's heart rate overtime or in response to applied stimulation signals.

Referring next to FIG. 2B, the lead assembly 13 delivers an electricalsignal from the neurostimulator 12 to the vagus nerve 15, 16 via theelectrodes 14. On a proximal end, the lead assembly 13 has a leadconnector 27 that transitions an insulated electrical lead body to ametal connector pin 28 with a metal connector ring. During implantation,the connector pin 28 is guided through the receptacle 25 into the header24 and securely fastened in place using the setscrew (not shown) toelectrically couple one electrode of the lead assembly 13 to theneurostimulator 12 while a spring contact (not shown) makes electricalcontact to the ring connected to the other electrode. On a distal end,the lead assembly 13 terminates with the electrode 14, which bifurcatesinto a pair of anodic and cathodic electrodes 62 (as further describedinfra with reference to FIG. 4 ). In one embodiment, the lead connector27 is manufactured using silicone and the connector pin 28 and ring aremade of stainless steel, although other suitable materials could beused, as well. The insulated lead body 13 utilizes a silicone-insulatedalloy conductor material.

In some embodiments, the electrodes 14 are helical and placed around thecervical vagus nerve 15, 16 at the location below where the superior andinferior cardiac branches separate from the cervical vagus nerve. Inalternative embodiments, the helical electrodes may be placed at alocation above where one or both of the superior and inferior cardiacbranches separate from the cervical vagus nerve. In one embodiment, thehelical electrodes 14 are positioned around the patient's vagus nerveoriented with the end of the helical electrodes 14 facing the patient'shead. In an alternate embodiment, the helical electrodes 14 arepositioned around the patient's vagus nerve 15, 16 oriented with the endof the helical electrodes 14 facing the patient's heart 17. At thedistal end, the insulated electrical lead body 13 is bifurcated into apair of lead bodies that are connected to a pair of electrodes. Thepolarity of the electrodes could be configured into a proximal anode anda distal cathode, or a proximal cathode and a distal anode.

The neurostimulator 12 may be interrogated prior to implantation andthroughout the therapeutic period with a healthcare provider-operablecontrol system comprising an external programmer and programming wand(shown in FIG. 3 ) for checking proper operation, downloading recordeddata, diagnosing problems, and programming operational parameters. FIG.3 is a diagram showing an external programmer 40 for use with theimplantable neurostimulator 12 of FIG. 1 . The external programmer 40includes a healthcare provider operable programming computer 41 and aprogramming wand 42. Generally, use of the external programmer isrestricted to healthcare providers, while more limited manual control isprovided to the patient through “magnet mode.”

In one embodiment, the external programmer 40 executes applicationsoftware 45 specifically designed to interrogate the neurostimulator 12.The programming computer 41 interfaces to the programming wand 42through a wired or wireless data connection. The programming wand 42 canbe adapted from a Model 201 Programming Wand, manufactured and sold byCyberonics, Inc., and the application software 45 can be adapted fromthe Model 250 Programming Software suite, licensed by Cyberonics, Inc.Other configurations and combinations of external programmer 40,programming wand 42 and application software 45 are possible.

The programming computer 41 can be implemented using a general purposeprogrammable computer and can be a personal computer, laptop computer,ultrabook computer, netbook computer, handheld computer, tabletcomputer, smart phone, or other form of computational device. Theprogramming computer 41 functions through those componentsconventionally found in such devices, including, for instance, a centralprocessing unit, volatile and persistent memory, touch-sensitivedisplay, control buttons, peripheral input and output ports, and networkinterface. The computer 41 operates under the control of the applicationsoftware 45, which is executed as program code as a series of process ormethod modules or steps by the programmed computer hardware. Otherassemblages or configurations of computer hardware, firmware, andsoftware are possible.

Operationally, the programming computer 41, when connected to aneurostimulator 12 through wireless telemetry using the programming wand42, can be used by a healthcare provider to remotely interrogate theneurostimulator 12 and modify stored stimulation parameters. Theprogramming wand 42 provides data conversion between the digital dataaccepted by and output from the programming computer and the radiofrequency signal format that is required for communication with theneurostimulator 12. In other embodiments, the programming computer maycommunicate with the implanted neurostimulator 12 using other wirelesscommunication methods, such as wireless RF transmission. The programmingcomputer 41 may further be configured to receive inputs, such asphysiological signals received from patient sensors (e.g., implanted orexternal). These sensors may be configured to monitor one or morephysiological signals, e.g., vital signs, such as body temperature,pulse rate, respiration rate, blood pressure, etc. These sensors may becoupled directly to the programming computer 41 or may be coupled toanother instrument or computing device which receives the sensor inputand transmits the input to the programming computer 41. The programmingcomputer 41 may monitor, record, and/or respond to the physiologicalsignals in order to effectuate stimulation delivery in accordance withsome embodiments.

The healthcare provider operates the programming computer 41 through auser interface that includes a set of input controls 43 and a visualdisplay 44, which could be touch-sensitive, upon which to monitorprogress, view downloaded telemetry and recorded physiology, and reviewand modify programmable stimulation parameters. The telemetry caninclude reports on device history that provide patient identifier,implant date, model number, serial number, magnet activations, total ONtime, total operating time, manufacturing date, and device settings andstimulation statistics and on device diagnostics that include patientidentifier, model identifier, serial number, firmware build number,implant date, communication status, output current status, measuredcurrent delivered, lead impedance, and battery status. Other kinds oftelemetry or telemetry reports are possible.

During interrogation, the programming wand 42 is held by its handle 46and the bottom surface 47 of the programming wand 42 is placed on thepatient's chest over the location of the implanted neurostimulator 12. Aset of indicator lights 49 can assist with proper positioning of thewand and a set of input controls 48 enable the programming wand 42 to beoperated directly, rather than requiring the healthcare provider toawkwardly coordinate physical wand manipulation with control inputs viathe programming computer 41. The sending of programming instructions andreceipt of telemetry information occur wirelessly through radiofrequency signal interfacing. Other programming computer and programmingwand operations are possible.

FIG. 4 is a diagram showing the helical electrodes 14 provided as on thestimulation lead assembly 13 of FIG. 2 in place on a vagus nerve 15, 16in situ 50. Although described with reference to a specific manner andorientation of implantation, the specific surgical approach andimplantation site selection particulars may vary, depending uponphysician discretion and patient physical structure.

Under one embodiment, helical electrodes 14 may be positioned on thepatient's vagus nerve 61 oriented with the end of the helical electrodes14 facing the patient's head. At the distal end, the insulatedelectrical lead body 13 is bifurcated into a pair of lead bodies 57, 58that are connected to a pair of electrodes 51, 52. The polarity of theelectrodes 51, 52 could be configured into a proximal anode and a distalcathode, or a proximal cathode and a distal anode. In addition, ananchor tether 53 is fastened over or in connection with the lead bodies57, 58 that maintains the helical electrodes' position on the vagusnerve 61 following implant. In one embodiment, the conductors of theelectrodes 51, 52 are manufactured using a platinum and iridium alloy,while the helical materials of the electrodes 51, 52 and the anchortether 53 are a silicone elastomer.

During surgery, the electrodes 51, 52 and the anchor tether 53 arecoiled around the vagus nerve 61 proximal to the patient's head, eachwith the assistance of a pair of sutures 54, 56, made of polyester orother suitable material, which help the surgeon to spread apart therespective helices. The lead bodies 57, 58 of the electrodes 51, 52 areoriented distal to the patient's head and aligned parallel to each otherand to the vagus nerve 61. A strain relief bend can be formed on thedistal end with the insulated electrical lead body 13 aligned, forexample, parallel to the helical electrodes 14 and attached to theadjacent fascia by a plurality of tie-downs 59 a-b.

The neurostimulator 12 delivers VNS under control of the electroniccircuitry 22. The stored stimulation parameters are programmable. Eachstimulation parameter can be independently programmed to define thecharacteristics of the cycles of therapeutic stimulation and inhibitionto ensure optimal stimulation for a patient 10. The programmablestimulation parameters include output current, signal frequency, pulsewidth, signal ON time, signal OFF time, magnet activation (for VNSspecifically triggered by “magnet mode”), and reset parameters. Otherprogrammable parameters are possible. In addition, sets or “profiles” ofpreselected stimulation parameters can be provided to physicians withthe external programmer and fine-tuned to a patient's physiologicalrequirements prior to being programmed into the neurostimulator 12.

Therapeutically, the VNS may be delivered as a multimodal set oftherapeutic doses, which are system output behaviors that arepre-specified within the neurostimulator 12 through the storedstimulation parameters and timing cycles implemented in firmware andexecuted by the microprocessor controller. The therapeutic doses includea maintenance dose that includes continuously-cycling, intermittent andperiodic cycles of electrical stimulation during periods in which thepulse amplitude is greater than 0 mA (“therapy ON”) and during periodsin which the pulse amplitude is 0 mA (“therapy OFF”).

The neurostimulator 12 can operate either with or without an integratedheart rate sensor. Additionally, where an integrated leadless heart ratemonitor is available, the neurostimulator 12 can provide autonomiccardiovascular drive evaluation and self-controlled titration. Finally,the neurostimulator 12 can be used to counter natural circadiansympathetic surge upon awakening and manage the risk of cardiacarrhythmias during or attendant to sleep, particularly sleep apneicepisodes.

Several classes of implantable medical devices provide therapy usingelectrical current as a stimulation vehicle. When such a systemstimulates certain organs or body structures like the vagus nerve,therapeutic levels of electrical stimulation are usually not welltolerated by patients without undergoing a process known as titration.Titration is a systematic method or process of incrementally increasingthe stimulation parameters employed by an implanted device to deliver astimulation current to the patient at increasing levels that achieve orimprove therapeutic benefit while minimizing side effects that coulddisrupt the stimulation therapy. Titration usually involves bringing thepatient to an initial stimulation level that is tolerable to the patient(i.e., below an initial tolerance threshold), waiting for a period oftime for the patient to adjust to the continuing delivery of the initialstimulation level and to define a higher tolerance threshold of thepatient, and then increasing the initial stimulation level to a higherstimulation level that is, in some patients, greater than the initialtolerance threshold, and so on. This process is repeated in sequencesthat progress from a stimulation delivery provided over a waitingperiod, and then to an increase in a stimulation level than defines thenext sequence of the stimulation delivery and the next waiting period.

FIG. 5 is a flow diagram showing a method for delivering vagus nervestimulation therapy, according to an exemplary embodiment. A titrationprocess 400 is used to gradually increase the stimulation intensity to adesired therapeutic level or maintenance dosage level. If thestimulation intensity is increased too quickly before the patient isfully accommodated to the stimulation signal, the patient may experienceundesirable side effects, such as coughing, hoarseness, throatirritation, or expiratory reflex. The titration process graduallyincreases stimulation intensity within a tolerable level, and maintainsthat intensity for a period of time to permit the patient to adjust toeach increase in intensity, thereby gradually increasing the patient'sside effect tolerance zone boundary to so as to accommodate subsequentincreases in intensity. The titration process continues until adequateadaptation is achieved. In embodiments, the titration process isautomated and is executed by the implanted device without manualadjustment of the stimulation intensity by the subject or health careprovider. As will be described in greater detail below, adequateadaptation is a composite threshold comprising one or more of thefollowing: an acceptable side effect level, a target intensity level,and a target physiological response. In some embodiments, adequateadaption includes all three objectives: an acceptable side effect level,a target intensity level, and a target physiological response.

In some embodiments, the titration process is a mix of automation andphysician input. As will be described in greater detail below, aphysician may use intermediate holds to stop the automated titration atcertain thresholds (e.g., a certain number of days or weeks, certainstimulation parameter values, etc.) and evaluate the patient beforeresuming the automated titration. The physician may receive a graphicaltitration history to review how the automated titration process has beenprogressing from one sequence to the next. The graphical titrationhistory may include markers. The markers may represent intermediateholds, when target parameters are reached between adjacent sequences,etc. After the physician has resumed the automatic titration, the nextsequence of automated titration may progress until the next intermediatehold is reached.

As described above, it may be desirable to minimize the amount of timerequired to complete the titration process so as to begin delivery ofthe stimulation at therapeutically desirable levels, particularly whenthe patient is being treated for an urgent condition such as CHF. Inaddition, it is desirable to utilize a maintenance dose intensity at theminimum level required to achieve the desired therapeutic effect. Thiscan reduce power requirements for the neurostimulator and reduce patientdiscomfort.

It has been observed that a patient's side effect profile is moresensitive to the stimulation output current than to the otherstimulation parameters, such as frequency, pulse width, and duty cycle.As a result, accommodation to the stimulation output current is aprimary factor in completing the titration process. It has also beenobserved that if the other stimulation parameters are maintained at alevel below the target levels, the output current can be increased tohigher levels without eliciting undesirable side effects that would beresult when the other parameters are at the target level. As a result,increasing the target output current while maintaining the otherstimulation parameters (pulse width in particular) at reduced levels canresult in a faster accommodation and shorter overall titration time thanwould be achieved by attempting to increase the output current whilestimulating at the target pulse width.

Referring again to FIG. 5 , in step 401, a stimulation system 11,including a neurostimulator 12, a nerve stimulation lead assembly 13,and a pair of electrodes 14, is implanted in the patient. In step 402,the patient undergoes an optional post-surgery recovery period, duringwhich time the surgical incisions are allowed to heal and no VNS therapyoccurs. This period may last, e.g., two weeks post surgery. In step 403,the stimulation therapy is initiated with the initiation of a titrationprocess. During this titration process, VNS therapy is titrated byadjusting one or more of the stimulation parameters, including outputcurrent, pulse width, signal frequency, and duty cycle, as will bedescribed in greater detail below. Completion of the titration processdetermines the stimulation intensity to be used for subsequentmaintenance doses delivered in step 404. These maintenance doses may beselected to provide the minimum stimulation intensity necessary toprovide the desired therapeutic result.

FIG. 6A is a flow diagram illustrating a titration process 500,according to an exemplary embodiment. Process 500 includes settingtitration parameters (step 501), initiating titration (step 502),stopping titration at an intermediate hold (step 503) and resumingtitration (step 504).

In step 501, a physician sets the titration parameters via programmer40, which are received by the implantable vagus nerve stimulation system11. In some embodiments, the titration parameters may be defined by oneor more titration algorithms that may be selected by the physician, ormay be presented to the physician as a preferred or recommended list oftitration parameters that the programming physician can adopt. In otherembodiments, rather than present the physician with a set titrationalgorithm with fixed algorithm values, the physician may be presentedwith default values that could be manually adjusted. The titrationparameter starting values, target values, and/or increment values foramplitude, pulse width, frequency, and/or duty cycle may be adjustable,as may the time interval between titration steps. Time of day and delayto therapy start may also be programmable as a titration parameter. Thetitration parameters may also include one or more intermediate holdsthat maintain certain parameters until the physician indicates that theautomated titration can continue. The physician may be limited so thatmodification can be made to only a select group of parameters, or someparameters may be considered to be in a locked state until unlocked bythe physician. In some embodiments, the physician is able to modify alarge number of titration parameters (e.g., 10-12 parameters).Alternatively, rather than give the physician control over the titrationparameter values themselves, the physician's options for the titrationprocess may be presented as a set of “aggressiveness” options to selectfrom, each of which would be used by the system to determine the valuesto use. For example, the physician may be able to choose from anaggressive profile, a moderate profile, or a light profile (sensitive)that is appropriate for certain types of patients that do not requiredetailed titration parameter programming. More or fewer aggressivenessprofiles could be used, and the aggressiveness profiles may correspondto the overall health status of the patient, the patient's sensitivityto stimulation therapies or titration processes, or the patient'smedical history. The aggressiveness profile selected by the physicianmay result in a predetermined set of titration parameters beingselected. The predetermined titration parameters may vary betweendifferent aggressiveness profiles, and some titration parameters mayremain constant, or similar, between various aggressiveness profiles.For example, the aggressive profile may be suitable for patients thathave a high toleration for the titration process and may include shortertime intervals between titration steps, higher intensity target values,and/or larger increment values (e.g., as compared to the moderate orlight profiles) that may result in an achievement of a suitable therapylevel more quickly as compared to the moderate or light profiles. Whilesome of the parameters may promote a more aggressive titrationprogression, some of the parameters may be consistent with parameters ofother profiles (e.g., titration holds). In some embodiments, each of theaggressiveness profiles may be mapped by the system to a set ofparameters or a range of parameters. For example, if the user selectsthe aggressive profile, the system may receive the user selection andset the values of one or more parameters (e.g., amplitude, pulse width,frequency, duty cycle, intervals between titration steps, and/or otherparameters) to a first set of values. If the user selects the moderateprofile, the system may set the values of the parameters to a secondpredetermined set or range of values that is different than the setassociated with the aggressive profile. In some embodiments, thephysicians are limited to modification of the parameters within a rangeof boundary values. The ranges may be for the default parameters, or maybe set individually for the aggressiveness options (e.g., the ranges forthe aggressive profile and the moderate profile may be different, butmay overlap for some parameters). The physician may be able to customizethe parameters in the preset profiles. In step 502, the physicianinitiates titration using the titration parameters defined at 501.

In step 503, titration is stopped at a titration hold. The titrationhold may be an intermediate hold set by the physician during step 501.The VNS system 11 may perform automated titration according to process600, described below. However, the physician is given the option(through the programmer 40) to designate intermediate points at whichthe titration algorithm would pause and await manual (programmer-based)activation by the physician. These hold points may be either time based(e.g. after 2, 4, 6, and/or 8 weeks of titration) or stimulation based(e.g. once stimulation amplitude reaches 1.0, 1.5, 2.0, and/or 2.5 mA).This would allow the physician to evaluate the patient in the clinicbefore deciding to continue titration. The physician releases the holdon the titration with the programmer 40 once the patient has beenevaluated. The physician may also modify parameters during the clinicalevaluations.

The holds may be predefined for the entire titration process duringinitial set up. Alternatively, the physician may have the option ofsetting a new intermediate hold when evaluating the patient. Theintermediate holds may be consistent throughout the titration process(e.g., every 2 weeks, every 0.5 mA, etc.). In another embodiment, theintermediate holds are different for at least one hold (e.g., 4 weeks tothe first hold, 2 weeks for every subsequent hold, etc.). In anotherembodiment, intermediate holds can be a combination of parameters (e.g.,amplitude and pulse width). In some embodiments, the hold may be set tobegin when both parameters are met, or when one parameter is met. Inanother embodiment, one parameter cannot exceed the hold value and willremain constant until the second parameter is reached. In someembodiments, both parameters will progress according to the automatedtitration until both parameters meet the intermediate hold value, butone parameter may exceed the intermediate hold until the secondparameter reaches the intermediate hold value. The physician may havethe option to set as many or as few intermediate holds as desired.

During the automated titration between intermediate holds, the VNSsystem 11 may be fully automated or partially automated. In someembodiments, titration is performed without any intervention from eitherthe patient or the healthcare provider. This embodiment alsoautomatically detects patient side effects and intolerance, and adjustsstimulation parameters to remain below the side effect threshold, as isdescribed with respect to FIG. 6B. In another embodiment, the VNS system11 may automatically adjust stimulation parameters slowly over time,without any additional intervention from the healthcare provider.Because the system may not be able to determine if stimulation causes anintolerable side effect, it may be configured to rely on the patient toswipe a magnet to indicate an intolerable level of a side effect. TheVNS system 11 may then adjust stimulation parameters in response topatient magnet activation.

For example, patients may require a total of 10±2 clinic visits over a10-week period to reach the target stimulation intensity. The frequencyof required clinic visits is bothersome to both patients and providers,and creates a barrier to therapy adoption. In addition, the frequency ofrequired clinic visits extends the time required to titrate patients tothe target stimulation intensity. However, physician may be skeptical ofcompletely automated titration and want to ensure the patients are notexperiencing intolerable side effects and are adapting to stimulationadequately. By allowing the physician to set the parameters, andevaluate the patient intermediately, but still allow titration toperform automatically between visits, the time period to reach thetarget stimulation may be reduced, while giving the physicians morecontrol over the titration process. Preferably, the number of clinicvisits needed and the overall timeframe of the titration process isreduced by only the use of intermediate holds. Any time penalty relatedto the intermediate holds is believed to be significantly less than thetime penalty resulting from an automated titration process that causesside effect and ultimately requires the patient to undergo are-titration protocol.

In step 504, titration is resumed. The physician may resume titrationusing the programmer 40 after evaluation of the patient. When thephysician resumes titration, they may have the option to modifystimulation parameters and/or intermediate holds. The titration mayresume using automated titration until the next intermediate hold isreached. This process may continue until the therapy parameters arereached.

FIG. 6B is a flow diagram illustrating a titration process 600 inaccordance with exemplary embodiments. When first initiating thetitration process, the neurostimulator 11 is configured to generate astimulation signal having an initial stimulation parameter set. Theinitial parameter set may comprise an initial output current, an initialfrequency, an initial pulse width, and an initial duty cycle. Thevarious initial parameter settings may vary, but may be selected so thatone or more of the parameters are set at levels below a predefinedtarget parameter set level, such that the titration process is used togradually increase the intensity parameters to achieve adequateadaptation. In some embodiments, the initial frequency is set at thetarget frequency level, while the initial output current, initial pulsewidth, and initial duty cycle are set below their respective targetlevels. In one embodiment, the target parameter set comprises a 10 Hzfrequency, 250 μsec pulse width, a duty cycle of 14 sec ON and 1.1minutes OFF, and an output current of between 1.5 mA-3.0 mA (e.g., 2.5mA for right side stimulation and 3.0 mA for left side stimulation), andthe initial parameter set comprises 10 Hz frequency, 130 μsec pulsewidth, a duty cycle of 14 sec ON and 1.1 minutes OFF, and an outputcurrent of between 0.25 mA-0.5 mA. In other embodiments, the targetparameter set includes a 5 Hz frequency that is used instead of a 10 Hzfrequency. The initial parameter set may also include one or moreintermediate holds as discussed with respect to FIG. 6A. However, thisis an exemplary embodiment and these values are not intended to belimiting. Other frequencies, pulse widths, duty cycles and outputcurrents may be implemented. The initial and target parameters may varyfrom patient to patient based on the patient's sensitivity tostimulation. While the initial parameters are shown to be equal to thetarget parameters for some of the exemplary parameters (e.g., frequencyand duty cycle), some or all of the parameters may have initialparameters that differ from the target parameters.

In step 601, the stimulation system delivers stimulation to the patient.If this is the first titration session, then the stimulation would bedelivered with the initial stimulation parameter set described above. Ifthis is a subsequent titration session, then the stimulation intensitywould remain at the same level provided at the conclusion of theprevious titration session. Alternatively, the subsequent titrationsession can start at a level that is set by the physician, e.g., at thenext titration level that follows the level provided at the conclusionof the previous titration session.

In step 602, the output current is gradually increased until thestimulation results in an intolerable side effect level, the targetoutput current (e.g., 2.5 mA) is reached, or adequate adaptation isachieved. As described above, adequate adaptation is a compositethreshold comprising one or more of the following: an acceptable sideeffect level, a target intensity level, and a target physiologicalresponse. In accordance with some embodiments, the target physiologicalresponse comprises a target heart rate change during stimulation. Thepatient's heart rate may be monitored using an implanted or externalheart rate monitor, and the patient's heart rate during stimulation iscompared to the patient's baseline heart rate to determine the extent ofheart rate change. In accordance with some embodiments, the target heartrate change is a heart rate change of between 4% and 5%. If at any pointduring the titration process 600 adequate adaptation is achieved, thetitration process ends and the stimulation intensity which resulted inthe adequate adaptation is used for ongoing maintenance dose therapydelivery.

The output current may be increased in any desired increment, but smallincrements, e.g., 0.1 mA or 0.25 mA, may be desirable so as to enablemore precise adjustments. In some cases, the output current incrementsmay be determined by the neurostimulator's maximum control capability.During the initial titration sessions, it is likely that the patient'sside effect tolerance zone boundary will be reached well before theoutput current reaches the target level or adequate adaptation isachieved. At decision step 603, if the target output current has notbeen achieved but the maximum tolerable side effects have been exceeded,the process proceeds to step 604.

In step 604, the output current is reduced one increment to bring theside effects within acceptable levels. In addition, the frequency isreduced. In embodiments in which the initial frequency was 10 Hz, instep 604, the frequency may be reduced, e.g., to 5 Hz or 2 Hz.

Next, in step 605, the output current is gradually increased again atthe reduced frequency level until the stimulation results in anintolerable side effect level or the target output current (e.g., 2.5mA) is reached. At decision step 606, if the target output current hasbeen reached and the maximum tolerable side effects have not beenexceeded, the process proceeds to step 607 where the titration sessionis concluded. The stimulation system may be programmed to continuedelivering the stimulation signal at the last parameter settingsachieved prior to conclusion of the titration session. After a period oftime, another titration session may be initiated and the process returnsto step 601. This can be any period of time sufficient to permit thepatient to adjust to the increased stimulation levels. This can be, forexample, as little as approximately two or three days, approximately oneto two weeks, approximately four to eight weeks, or any other desiredperiod of time.

In some embodiments, the titration sessions are automatically initiatedby the stimulation system or initiated by the patient without requiringany intervention by the health care provider. This can eliminate theneed for the patient to schedule a subsequent visit to the health careprovider, thereby potentially reducing the total amount of time neededfor the titration process to complete. In these embodiments, thestimulation system may include a physiological monitor, e.g., animplanted heart rate sensor, that communicates with the stimulationsystem's control system to enable the control system to detect thepatient's physiological response to the titration and automatically makeadjustments to the titration processes described herein with reduced orno inputs from the patient or health care provider. The monitoredsignals can also enable the control system to detect when the targetphysiological response has been achieved and conclude the titrationprocess. The stimulation system could in addition or alternativelyinclude a patient control input to permit the patient to communicate tothe control system that the acceptable side effect level has beenexceeded. This control input may comprise an external control magnetthat the patient can swipe over the implanted neurostimulator, or otherinternal or external communication device that the patient can use toprovide an input to the control system. In these automatically initiatedtitration sessions, the stimulation system may be configured to wait aperiod of time after completing one session before initiating the nextsession. This period of time may be predetermined, e.g., two or threedays, or programmable. In another embodiment, the stimulation system isconfigured to wait until authorization has been received beforeinitiating the next session (i.e., an intermediate hold).

Returning to decision step 606, if the target output current has notbeen reached but the maximum tolerable side effects have been exceeded,the process proceeds to step 608. In step 608, the output current isreduced one increment to restore an acceptable side effect condition,and the frequency is gradually increased until the stimulation resultsin an intolerable side effect level or the target frequency (e.g., 10Hz) is reached. At decision step 609, if the target frequency has notbeen reached but the maximum tolerable side effects have been exceeded,the frequency is reduced to restore an acceptable side effect level andthe process proceeds to step 607. Again, in step 607, the currenttitration session is concluded and the stimulation system may beprogrammed to continue delivering the stimulation signal at the lastparameter settings achieved prior to conclusion of the titrationsession.

At decision step 609, if the target frequency has been reached beforethe maximum tolerable side effects have been exceeded, the duty cycle isgradually increased until the stimulation results in an intolerable sideeffect level or the target duty cycle (e.g., 14 sec ON and 1.1 min OFF)is reached, at which point the process proceeds to step 607 and thetitration session is concluded and ongoing stimulation delivered at thelast intensity eliciting acceptable side effect levels.

Returning to decision step 603, if the target output current has beenachieved before the maximum tolerable side effects are exceeded, theprocess proceeds to step 611. In step 611, the pulse width is graduallyincreased until the stimulation results in an intolerable side effectlevel or the target pulse width (e.g., 250 μsec) is reached. In someembodiments, before step 611, the output current is reduced (e.g., by upto 50%), and the pulse width may be increased in step 611 at thatreduced output current. After the target pulse width is achieved, theoutput current may be restored to the target output current. In otherembodiments, the output current may be reduced (or may be retained atthe reduced level established prior to step 611, as described above),and the frequency and duty cycle are gradually increased in step 613 atthat reduced output current. This reduction in output current afterachieving the target output current may enable the patient to maintaintolerability with increasing pulse width, frequency, and duty cycle insubsequent titration steps.

At decision step 612, if the target pulse width has not been achievedbefore the maximum tolerable side effects have been exceeded, the pulsewidth is reduced to restore an acceptable side effect level and theprocess proceeds to step 607. Again, in step 607, the current titrationsession is concluded.

If at decision step 612, the target pulse width has been achieved beforethe maximum tolerable side effects have been exceeded, the processproceeds to step 613. In step 613, the frequency and/or duty cycle areincreased until the stimulation results in an intolerable side effectlevel or the target frequency and target duty cycle are reached. Thefrequency and duty cycle can be increased in step 612 simultaneously,sequentially, or on an alternating basis.

At decision step 614, if the target frequency and/or target duty cyclehave not been achieved before the maximum tolerable side effects havebeen exceeded, the pulse width and/or frequency are reduced to restorean acceptable side effect level and the process continues to step 607and the titration session is concluded. In some embodiments, theconclusion of the titration session represented in step 607 indicates anintermediate hold has been reached. A new titration session could thenbe initiated after visiting a physician to release the intermediatehold.

At decision step 614, if the target pulse width and target frequencyhave been achieved before the maximum tolerable side effects have beenexceeded, all of the stimulation parameters will have reached theirtarget levels and the titration process concludes at step 615. Thestimulation therapy may proceed with the maintenance dose at the targetstimulation levels. In some embodiments, the target frequency and dutycycle achieved are for a given titration session with an intermediatehold. In this case, the patient would visit a health care provider orphysician for an evaluation. The physician would then release the holdon the titration processes, or initiate the beginning of therapy.

In some embodiments, in step 604, instead of reducing the frequency inorder to facilitate increase of the output current, the pulse width maybe reduced. For example, embodiments where the target pulse width is 250μsec, the pulse width may be reduced, e.g., to 150 μsec or less. Then,the method proceeds to step 605, in which the output current isgradually increased again at the reduced pulse width level until thestimulation results in an intolerable side effect level or the targetoutput current (e.g., 2.5 mA) is reached.

Therapy can also be autonomously titrated by the neurostimulator 12 inwhich titration progressively occurs in a self-paced, self-monitoredfashion. The progression of titration sessions may occur on anautonomous schedule or may be initiated upon receipt of an input fromthe patient. Ordinarily, the patient 10 is expected to visit hishealthcare provider to have the stimulation parameters stored by theneurostimulator 12 in the recordable memory 29 reprogrammed using anexternal programmer. Alternatively, the neurostimulator 12 can beprogrammed to automatically titrate therapy by up titrating the VNSthrough periodic incremental increases using titration sessions asdescribed above. The titration process 600 will continue until theultimate therapeutic goal is reached.

Following the titration period, therapeutic VNS, as parametricallydefined by the maintenance dose operating mode, is delivered to at leastone of the vagus nerves. The stimulation system 11 delivers electricaltherapeutic stimulation to the cervical vagus nerve of a patient 10 in amanner that results in creation and propagation (in both afferent andefferent directions) of action potentials within neuronal fibers ofeither the left or right vagus nerve independent of cardiac cycle.

FIG. 7A is a simplified block diagram of an implanted neurostimulationsystem 700, according to an exemplary embodiment. The implantedneurostimulation system 700 comprises a control system 702 comprising aprocessor programmed to operate the system 700, a memory 703, anoptional physiological sensor 704, and a stimulation subsystem 706. Thephysiological sensor 704 may be configured to monitor any of a varietyof patient physiological signals and the stimulation subsystem 706 maybe configured to deliver a stimulation signal to the patient. In oneexample, the physiological sensor 704 comprises an ECG sensor or anaccelerometer for monitoring heart rate and the stimulation subsystem706 comprises a neurostimulator 12 programmed to deliver ON-OFF cyclesof stimulation to the patient's vagus nerve. The implanted system 700may include a patient input sensor 705, described in more detail below.

The control system 702 is programmed to activate the neurostimulator 12to deliver stimulation signals at varying stimulation intensities to thepatient and to monitor the physiological signals in response to thosedelivered stimulation signals.

The external programmer 707 shown in FIG. 7A may be utilized by aclinician or by the patient for communicating with the implanted system700 to adjust parameters, activate therapy, retrieve data collected bythe system 700 or provide other input to the system 700. In someembodiments, the external programmer 707 may be used remote from theimplanted system 700 (e.g., when the patient is not at a clinic). Forexample, instead of the patient coming into the clinic for a check-upduring a titration hold, the clinician may check on the patient remotely(e.g., phone call, video call, etc.). The clinician could then use theexternal programmer 707 to activate the next titration session, ormodify parameters of the titration. In some embodiments, the externalprogrammer 707 may provide an alert indicating the patient has reached atitration hold. In some embodiments, the patient receives an alertindicating a titration hold has been reached (e.g., email, text message,etc.). In some such embodiments, the external programmer 707 may includecommunication circuitry adapted to communicate over a long distanceusing one or more protocols (e.g., cellular, Internet, etc.). In someembodiments, the external programmer 707 may be configured to programthe implanted system 700 with a prescribed time or window of time duringwhich titration sessions may be initiated. This can be used to prevent atitration session from occurring at night when the patient's sleep islikely to be disturbed by the increase in stimulation intensity andresulting side effects.

Patient inputs to the implanted system 700 may be provided in a varietyof ways. The implanted system 700 may include a patient input sensor705. As described above, a patient magnet 730 may be used to provideexternal input to the system 700. When the patient magnet 730 is placedon the patient's chest in close proximity to the implanted system 700,the patient input sensor 705 will detect the presence of the magneticfield generated by the patient magnet 730 and provide a control input tothe control system 702. The system 700 may be programmed to receivepatient inputs to set the time of day during which titration sessionsare to be initiated.

In other embodiments, the patient input sensor 705 may comprise a motionsensor, such as an accelerometer, which is configured to detect tappingon the surface of the patient's chest. The patient may use finger tapsin one or more predetermined patterns to provide control inputs to theimplanted system 700. For example, when the motion sensor detects threerapid taps to the patient's chest, that may trigger an operation on theimplanted system 700 (e.g., to initiate a titration session).Alternatively, if the motion sensor detects a predetermined pattern oftaps during a titration session, the implanted system 700 will interpretthose taps as a patient input indicating that the patient's tolerancezone boundary has been exceeded.

In other embodiments, the patient input sensor 705 may comprise anacoustic transducer or other sensor configured to detect acousticsignals. The system 700 may be programmed to interpret the detection ofcertain sounds as patient inputs. For example, the patient may utilizean electronic device, such as a smartphone or other portable audiodevice, to generate one or more predetermined sequences of tones. Thesystem 700 may be programmed to interpret each of these sequences oftones as a different patient input.

The titration of the stimulation signal delivery and the monitoring ofthe patient's physiological response (e.g., heart rate) may beadvantageously implemented using a control system 702 in communicationwith both the stimulation subsystem 706 and the physiological sensor704, such as by incorporating all of these components into a singleimplantable device 700. In accordance with other embodiments, anexternal control system 712 may be implemented in a separate implanteddevice or in an external programmer 720 or other external device, asshown in FIG. 7B to provide control over and communication with animplanted physiological sensor 714 and a stimulation subsystem 716similar to those describe with regard to FIG. 6A. The externalprogrammer 720 in FIG. 7B may be utilized by a clinician or by thepatient for adjusting stimulation parameters. The external programmer720 may be in wireless communication with the implanted medical device710, which includes the stimulation subsystem 716 and a memory 713. Inthe illustrated embodiment, the physiological sensor 714 is incorporatedinto the implanted medical device 710, but in other embodiments, thesensor 714 may be incorporated into a separate implanted device, may beprovided externally and in communication with the external programmer720, or may be provided as part of the external programmer 720.

While embodiments been particularly shown and described, those skilledin the art will understand that the foregoing and other changes in formand detail may be made therein without departing from the spirit andscope. For example, in various embodiments described above, thestimulation is applied to the vagus nerve. Alternatively, spinal cordstimulation (SCS) may be used in place of or in addition to vagus nervestimulation for the above-described therapies. SCS may utilizestimulating electrodes implanted in the epidural space, an electricalpulse generator implanted in the lower abdominal area or gluteal region,and conducting wires coupling the stimulating electrodes to thegenerator.

The present disclosure contemplates methods, systems, and programproducts on any machine-readable media for accomplishing variousoperations. The embodiments of the present disclosure may be implementedusing existing computer processors, or by a special purpose computerprocessor for an appropriate system, incorporated for this or anotherpurpose, or by a hardwired system. Embodiments within the scope of thepresent disclosure include program products comprising machine-readablemedia for carrying or having machine-executable instructions or datastructures stored thereon. Such machine-readable media can be anyavailable media that can be accessed by a general purpose or specialpurpose computer or other machine with a processor. By way of example,such machine-readable media can comprise RAM, ROM, EPROM, EEPROM, CD-ROMor other optical disk storage, magnetic disk storage or other magneticstorage devices, or any other medium which can be used to carry or storedesired program code in the form of machine-executable instructions ordata structures and which can be accessed by a general purpose orspecial purpose computer or other machine with a processor. Wheninformation is transferred or provided over a network or anothercommunications connection (either hardwired, wireless, or a combinationof hardwired or wireless) to a machine, the machine properly views theconnection as a machine-readable medium. Thus, any such connection isproperly termed a machine-readable medium. Combinations of the above arealso included within the scope of machine-readable media.Machine-executable instructions include, for example, instructions anddata which cause a general purpose computer, special purpose computer,or special purpose processing machines to perform a certain function orgroup of functions.

Although the figures may show a specific order of method steps, theorder of the steps may differ from what is depicted. Also two or moresteps may be performed concurrently or with partial concurrence. Suchvariation will depend on the software and hardware systems chosen and ondesigner choice. All such variations are within the scope of thedisclosure. Likewise, software implementations could be accomplishedwith standard programming techniques with rule based logic and otherlogic to accomplish the various connection steps, processing steps,comparison steps and decision steps.

Also, the term “or” is used in its inclusive sense (and not in itsexclusive sense) so that when used, for example, to connect a list ofelements, the term “or” means one, some, or all of the elements in thelist. Conjunctive language such as the phrase “at least one of X, Y, andZ,” unless specifically stated otherwise, is otherwise understood withthe context as used in general to convey that an item, term, etc. may beeither X, Y, Z, X and Y, X and Z, Y and Z, or X, Y, and Z. Thus, suchconjunctive language is not generally intended to imply that certainembodiments require at least one of X, at least one of Y, and at leastone of Z to each be present.

While various aspects and embodiments have been disclosed herein, otheraspects and embodiments will be apparent to those skilled in the art.The various aspects and embodiments disclosed herein are for purposes ofillustration and are not intended to be limiting, with the true scopeand spirit being indicated by the following claims.

What is claimed is:
 1. A method of titrating a neurostimulation signaldelivered to a patient from an implantable pulse generator, the methodcomprising: titrating the neurostimulation signal from a first set ofparameters toward a target set of parameters according to a titrationaggressiveness profile having a titration hold point; receiving a holdindicator indicating that the titration has reached the titration holdpoint; initiating an intermediate hold of the titrating of theneurostimulation signal in response to receiving the hold indicator; andreceiving an indication of a titration resumption that discontinues theintermediate hold.
 2. The method of claim 1, wherein the receiving ofthe indication of the titration resumption is preceded by a timeinterval sufficient to allow the patient to at least one of obtainassistance from a health care provider or activate a sensorcommunicating with the implantable pulse generator.
 3. The method ofclaim 1, further comprising: subsequent to receiving the indication ofthe titration resumption, delivering the neurostimulation signal at aholding set of stimulation parameters associated with the titration holdpoint; and titrating the neurostimulation signal from the holding set ofstimulation parameters toward the target set of parameters.
 4. Themethod of claim 3, wherein the hold indicator is a first hold indicator,the titration hold point is a first titration hold point, the holdingset of stimulation parameters is a first holding set of stimulationparameters, the intermediate hold is a first intermediate hold, and theindication of the titration resumption is a first indication of a firsttitration resumption; and wherein the method further comprises:receiving a second hold indicator, the second hold indicator indicatingthat at least one of the neurostimulation signal is being delivered at asecond holding set of stimulation parameters of a second titration holdpoint or a side effect is being experienced by the patient in responseto the neurostimulation signal; initiating a second intermediate hold ofthe titrating of the neurostimulation signal in response to the secondhold indicator; and receiving a second indication of a second titrationresumption that discontinues the second intermediate hold.
 5. The methodof claim 4, wherein the receiving of the second indication of the secondtitration resumption is preceded by a time interval sufficient to allowthe patient to at least one of obtain assistance from a health careprovider or activate a sensor communication with the implantable pulsegenerator.
 6. The method of claim 1, wherein the indication of thetitration resumption includes an instruction to modify theneurostimulation signal to a second set of parameters; and wherein themethod further comprises: subsequent to receiving the indication of thetitration resumption, delivering the neurostimulation signal at thesecond set of parameters; and titrating the neurostimulation signal fromthe second set of parameters toward the target set of parameters.
 7. Themethod of claim 6, wherein the hold indicator is a first hold indicator,the titration hold point is a first titration hold point, theintermediate hold is a first intermediate hold, and the indication ofthe titration resumption is a first indication of a first titrationresumption; and wherein the method further comprises: receiving a secondhold indicator, the second hold indicator indicating that at least oneof the neurostimulation signal is being delivered at a second holdingset of stimulation parameters of a second titration hold point or a sideeffect is being experienced by the patient in response to theneurostimulation signal; initiating a second intermediate hold of thetitrating of the neurostimulation signal in response to the second holdindicator; and receiving a second indication of a second titrationresumption that discontinues the second intermediate hold.
 8. The methodof claim 7, wherein the receiving of the second indication of the secondtitration resumption is preceded by a time interval sufficient to allowthe patient to at least one of obtain assistance from a health careprovider or activate a sensor communication with the implantable pulsegenerator.
 9. The method of claim 1, wherein the indication of thetitration resumption is received from an external device indicatinginstructions to discontinue the intermediate hold.
 10. The method ofclaim 1, wherein the titration aggressiveness profile has a moreaggressive level and a less aggressive level, the more aggressive leveldefined by at least one of the following as compared to the lessaggressive level: a shorter time interval associated with a transitionfrom the first set of parameters to the target set of parameters, agreater target intensity, or a greater increment value between parameterlevels at subsequent titration steps.
 11. A neurostimulation systemcapable of providing a neurostimulation signal to a patient, theneurostimulation system comprising: an implantable pulse generator thatgenerates the neurostimulation signal according to a titration protocolexecuted by a processor; an electrode configured to deliver theneurostimulation signal to the patient; and a lead coupling theelectrode to the implantable pulse generator, wherein the processor isconfigured to implement the titration protocol by issuing controlsignals that allow the implantable pulse generator to: titrate theneurostimulation signal from a first set of parameters toward a targetset of parameters according to a titration aggressiveness profile havinga titration hold point; receive a hold indicator indicating that thetitration has reached the titration hold point; initiate an intermediatehold of the titrating of the neurostimulation signal in response toreceiving the hold indicator; and receive an indication of a titrationresumption that discontinues the intermediate hold.
 12. Theneurostimulation system of claim 11, wherein the receiving of theindication of the titration resumption is preceded by a time intervalsufficient to allow the patient to at least one of obtain assistancefrom a health care provider or activate a sensor communicating with theimplantable pulse generator.
 13. The neurostimulation system of claim11, wherein the processor is further configured to issue additionalcontrol signals that allow the implantable pulse generator to:subsequent to receiving the indication of the titration resumption,deliver the neurostimulation signal at a holding set of stimulationparameters associated with the titration hold point; and titrate theneurostimulation signal from the holding set of stimulation parameterstoward the target set of parameters.
 14. The neurostimulation system ofclaim 13, wherein the hold indicator is a first hold indicator, thetitration hold point is a first titration hold point, the holding set ofstimulation parameters is a first holding set of stimulation parameters,the intermediate hold is a first intermediate hold, and the indicationof the titration resumption is a first indication of a first titrationresumption; and wherein the processor is still further configured toissue still additional control signals that allow the implantable pulsegenerator to: receive a second hold indicator, the second hold indicatorindicating that at least one of the neurostimulation signal is beingdelivered at a second holding set of stimulation parameters of a secondtitration hold point or a side effect is being experienced by thepatient in response to the neurostimulation signal; initiate a secondintermediate hold of the titrating of the neurostimulation signal inresponse to the second hold indicator; and receive a second indicationof a second titration resumption that discontinues the secondintermediate hold.
 15. The neurostimulation system of claim 14, whereinthe receiving of the second indication of the second titrationresumption is preceded by a time interval sufficient to allow thepatient to at least one of obtain assistance from a health care provideror activate a sensor communicating with the implantable pulse generator.16. The neurostimulation system of claim 11, wherein the indication ofthe titration resumption includes an instruction to modify theneurostimulation signal to a second set of parameters; and the processoris further configured to issue additional control signals that allow theimplantable pulse generator to: subsequent to receiving the indicationof the titration resumption, deliver the neurostimulation signal at thesecond set of parameters; and titrate the neurostimulation signal fromthe second set of parameters toward the target set of parameters. 17.The neurostimulation system of claim 16, wherein the hold indicator is afirst hold indicator, the titration hold point is a first titration holdpoint, the intermediate hold is a first intermediate hold, and theindication of the titration resumption is a first indication of a firsttitration resumption; and wherein the processor is still furtherconfigured to issue still additional control signals that allow theimplantable pulse generator to: receive a second hold indicator, thesecond hold indicator indicating that at least one of theneurostimulation signal is being delivered at a second holding set ofstimulation parameters of a second titration hold point or a side effectis being experienced by the patient in response to the neurostimulationsignal; initiate a second intermediate hold of the titrating of theneurostimulation signal in response to the second hold indicator; andreceive a second indication of a second titration resumption thatdiscontinues the second intermediate hold.
 18. The neurostimulationsystem of claim 17, wherein the receiving of the second indication ofthe second titration resumption is preceded by a time intervalsufficient to allow the patient to at least one of obtain assistancefrom a health care provider or activate a sensor communicating with theimplantable pulse generator.
 19. The neurostimulation system of claim11, wherein the indication of the titration resumption is received froma health care provider device indicating instructions from a health careprovider to discontinue the intermediate hold.
 20. The neurostimulationsystem of claim 11, wherein the titration aggressiveness profile has amore aggressive level and a less aggressive level, the more aggressivelevel defined by at least one of the following as compared to the lessaggressive level: a shorter time interval associated with a transitionfrom the first set of parameters to the target set of parameters, agreater target intensity, or a greater increment value between parameterlevels at subsequent titration steps.